Compositions and methods for increasing compliance with therapies using aldehyde dehydrogenase inhibitors and treating alcoholism

ABSTRACT

Compositions and methods for treating, preventing, or reducing alcoholism, in particular methods for increasing patient compliance with therapies that require the intake of an ALDH inhibitor comprising the step of administering a monoamine oxidase B inhibitor.

RELATED APPLICATIONS

[0001] This patent application claims the benefit of the filing date ofU.S. Patent Application No. 60/338,901 filed on Nov. 5, 2001, the entirecontents of which are hereby expressly incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to compositions and methods forincreasing patient compliance with therapies comprising theadministration of aldehyde dehydrogenase inhibitors, and for preventing,ameliorating or treating alcoholism. Such compositions and methods maybe used to facilitate alcohol cessation, and may comprise a combinationof aldehyde dehydrogenase inhibitors and monoamine oxidase inhibitors.

[0004] 2. Description of the Related Art

[0005] Alcohol is a commonly abused drug. According to the Diagnosticand Statistical Manual of Mental Disorders (DSM-IV), problematic alcoholuse is divided into alcohol abuse and alcohol dependence.

[0006] Alcohol abuse involves recurrent alcohol consumption thatnegatively affects one's life, whereas alcohol dependence includesalcohol abuse and additionally symptoms of tolerance and withdrawal[McRae et al., “Alcohol and Substance Abuse,” In: Advances in thePathophysiology and Treatment of Psychiatric Disorders: Implications forInternal Medicine, 85(3):779-801 (2001); Swift, R. M., New England J.Med 340:1482-1490 (1999); Kick, S., Hospital Practice 95-106 (1999)]. In1997, the estimated lifetime prevalence for alcohol abuse was 9.4% andfor alcohol dependence was 14.1%, with men having significantly higherrates of dependence than women [McRae et al., supra]. Alcohol abuse anddependence commonly lead to other problems such as alcohol-relatedviolence, motor vehicle accidents, and medical consequences of chronicalcohol ingestion including death [McRae et al., supra; Swift, supra].

[0007] One of the pharmacotherapies that have been suggested fortreating alcoholism, including facilitating alcohol cessation, is theadministration of agents that inhibiting the enzyme aldehydedehydrogenase (ALDH), an enzyme involved in the removal of acetaldehyde,a toxic metabolite of alcohol. Examples of ALDH inhibitors include,e.g., disulfiram, coprine, cyanamide, 1-aminocyclopropanol (ACP),daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, andany of their metabolites or analogs exhibiting ALDH-inhibiting activityincluding, e.g., S-methyl N,N-diethyldithiocarbamate, S-methylN,N-diethyldithiocarbamate sulfoxide, and S-methylN,N-diethylthiocarbamate sulfoxide. Patients who consume such inhibitorsof ALDH experience mild to severe discomfort if they ingest alcohol. Theefficacy of therapies using ALDH inhibitors depends on the patient's ownmotivation to self-administer the ALDH inhibitors, e.g., oral forms ofthe inhibitors, or to receive additional therapies, e.g., DEPO forms ofdisulfiram. In fact, patient compliance is a significant problem withthese types of therapies.

[0008] Although multiple forms of ALDH exist. ALDH-I (also known asALDH-2) and ALDH-II (also known as ALDH-1) are the major enzymesresponsible for the oxidation of acetaldehyde. ALDH-I has a higheraffinity for acetaldehyde than ALDH-II, and is thought to be the primaryenzyme involved in alcohol detoxification [Keung, W. M., et al., Proc.Natl. Acad. Sci. USA 95:2198-2203 (1998)]. The discovery that 50% of theAsian population carries a mutation in ALDH-I that inactivates theenzyme, together with the low occurrence of alcohol abuse in thispopulation supports the contention that it is this isozyme of ALDH thatis primarily responsible for alcohol detoxification. Recent studies alsoimplicate ALDH-I in the metabolism of monoamine neurotransmitters suchas serotonin (5-HT) and dopamine (DA) [Keung, W. M., et al., Proc. Natl.Acad. Sci. USA 95:2198-2203 (1998)].

[0009] Disulfiram, also known as tetraethylthioperoxydicarbonic diamide,bis-diethylthiocarbamoyl disulfide, tetraethylthiuram disulfide,Cronetal™, Abstenil™, Stopetyl™, Contrain™, Antadix™, Anietanol™,Exhoran™, ethyl thiurad, Antabuse™, Etabuse™, RO-sulfiram, Abstinyl™,Thiuranide™, Esperal™, Tetradine™, Noxal™, Tetraeti™ [Swift, supra], isa potent irreversible inhibitor of ALDH-II and inhibits ALDH-I onlyslightly. Recent studies suggest that the inhibition of ALDH-I bydisulfiram occurs indirectly via its metabolites, e.g.,S-methyl-N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) [Yourick et al.,Alcohol 4:463 (1987); Yourick et al., Biochem. Pharmacol. 38:413 (1989);Hart et al., Alcohol 7:165 (1990); Madan et al., Drug Metab. Dispos.23:1153-1162 (1995)]. Ingestion of alcohol while taking disulfiramresults in the accumulation of aldehydes, which causes tachycardia,flushing, diaphoresis, dyspnea, nausea and vomiting (also knowncollectively as the disulfiram or disulfiram-ethanol reaction).

[0010] Although disulfiram has been available in the United States formany decades, patients frequently have difficulty complying withdisulfiram treatment therapies. One reason for poor compliance is thelack of motivation for the patient to continue to take disulfiram, thatis, other than self-motivation (i.e., there is no positive reinforcementfor taking disulfiram). Another reason is because of the discomfort thatarises if the patient ingests alcohol during disulfiram therapy [McRaeet al., supra; Swift, R. M., supra; Kick, S., supra]. In fact,disulfiram has not proven to be useful in maintaining long-term sobriety[Kick, supra].

[0011] Coprine (N5-(hydroxycyclopropyl)-L-glutamine) has been shown toinhibit ALDH via its active metabolite, 1-aminocyclopropanol (ACP). U.S.Pat. No. 4,076,840 describes the synthesis and use of cyclopropylbenzamides, including coprine, for the treatment of alcoholism. In ratstudies, coprine effectively suppressed ethanol consumption, and wasshown to be a more potent inhibitor of ALDH as compared to disulfiram[Sinclair et al., Adv. Exp. Med. Biol. 132:481-487 (1980); U.S. Pat. No.4,076,840].

[0012] Cyanamide has been described as an alcohol-sensitizing agent thatis less toxic than disulfiram [Ferguson, Canad. M.A.J. 74:793-795(1956); Reilly, Lancet 911-912 (1976)]. Although cyanamide is unable toinhibit either ALDH-I or ALDH-II in vitro, a reactive product ofcyanamide catabolism inhibits both isozymes in vivo, indicating thatcyanamide inhibits ALDH via a reactive species [DeMaster et al.,Biochem. Biophys. Res. Com. 107:1333-1339 (1982)]. Cyanamide has beenused for treating alcoholism but has not been approved in the U.S.Citrated calcium cyanamide is marketed in other countries as Temposil™,Dipsane™ and Abstem™, and plain cyanamide is marketed as Colme™ in Spain[See, U.S. Pat. No. 6,255,497].

[0013] Daidzin is a selective potent reversible inhibitor of ALDH-I,originally purified from an ancient Chinese herbal treatment for alcoholabuse. Its analogs include daidzein-7-O-[ω-carboxynonyl] ether(deczein), daidzein-7-O-[ω-carboxyhexyl] ether (hepzein),daidzein-7-O-[ω-carboxypentyl] ether (hexzein), daidzein, puerarin, anddicarboxymethyl-daidzein [Keung, Chemico-Bio. Int.130-132:919-930(2001)]. U.S. Pat. Nos. 5,204,369; 5,886,028; 6,121,010; and 6,255,497describe methods for treating alcohol dependence or abuse using thesecompounds.

[0014] One of the major problems associated with therapies using ALDHinhibitors is ensuring patient compliance with the regimen. According toapplicant's knowledge, there have been no teachings that suggestpharmacotherapies that adequately address this problem. For example, WO99/21540 describes the administration of disulfiram in combination withcompounds that bind to the D1 and/or D5 receptors and mimic dopamine toreduce craving for addictive substances in mammals. However, WO 99/21540does not suggest pharmacotherapy for ensuring patient compliance withthe regimen, which is important for the success of the treatment.

[0015] Another pharmacotherapy that has been suggested for treatingalcoholism involves the inhibition of monoamine oxidases (MAOs). MAOscatalyze the oxidation of a variety of monoamines, includingepinephrine, norepinephrine, serotonin and dopamine. MAOs are ironcontaining enzymes that exist as two isozymes A (MAOA) and B (MAOB).Various publications have described treatments for alcoholism using MAOBinhibitors [e.g, WO 92/21333, WO 96/37199]. WO 96/35425 discusses atreatment for alcoholism using a selective MAOB inhibitor in combinationwith a partial agonist of the 5-TH1A receptor. WO 00/71109 discusses atreatment for alcohol withdrawal symptoms using the MAOB inhibitordesmethylselegiline in combination with a second drug that treatsalcohol withdrawal symptoms. U.S. Pat. No. 6,239,181 describes methodsfor alleviating symptoms associated with alcoholic neuropathy byadministering the MAOB inhibitor, selegiline. However, none of the abovereferences teach or suggest the use of MAOB inhibitors in therapiesusing ALDH inhibitors. Moreover, none of these references teach thatMAOB inhibitors have a sustained effect on ensuring patient compliancewith other therapies.

[0016] The present invention provides a solution for the deficiencies intraditional therapies using ALDH inhibitors to stop, prevent or reducerecidivism, thus, promoting compliance. The present invention alsoprovides unexpectedly new and better compositions and methods fortreating diseases that require the self-administration of an ALDHinhibitor.

SUMMARY OF THE INVENTION

[0017] The present invention provides compositions and methods forpreventing, treating or reducing alcoholism comprising administering atherapeutically effective amount of an ALDH inhibitor in combinationwith an MAOB inhibitor.

[0018] There is provided in one embodiment of the present inventioncompositions and methods for increasing the rate of continuousabstinence, delaying resumption of abuse or dependence and/or preventingrelapses in patients being treated for alcoholism.

[0019] There is further provided a method for increasing patientcompliance with therapies that require self-administration of an ALDHinhibitor comprising the step of administering a therapeuticallyeffective amount of a MAOB inhibitor.

[0020] According to one embodiment of the invention, the patient to betreated suffers from a disease requiring treatment with an ALDHinhibitor and consumes or can consume alcohol during therapy. Thetherapy does not involve forcing the patient to intake alcohol as partof the treatment. According to one preferred embodiment of thisinvention, the patient to be treated is suffering from alcoholism.

[0021] A composition according to the latter embodiment of the inventioncomprises an MAOB inhibitor and an ALDH inhibitor. The ALDH inhibitormay inhibit ALDH-I. The ALDH inhibitor may be, e.g., disulfiram,coprine, cyanamide, 1-aminocyclopropanol (ACP), daidzin, cephalosporins,antidiabetic sulfonyl ureas, metronidazole, or any of their metabolitesor analogs exhibiting ALDH-inhibiting activity including, e.g., S-methylN,N-diethyldithiocarbamate, S-methyl N,N-diethyldithiocarbamatesulfoxide, or S-methyl N,N-diethylthiocarbamate sulfoxide. In a morepreferred embodiment, the ALDH inhibitor is disulfiram or anALDH-inhibiting metabolite thereof. According to one preferredembodiment, the amount of disulfiram or an ALDH-inhibiting metabolitethereof administered is 500 mg per day.

[0022] In one embodiment, the MAOB inhibitor is, e.g., selegiline,pargyline, desmethylselegiline, rasagiline [R(+)N-propargyl-laminoindan], 3-N-phenylacetylamino-2,5-piperidinedione orcaroxyazone. In a more preferred embodiment, the MAOB inhibitor isselegiline. According to one preferred embodiment, the amount ofselegiline administered is 15 mg or less per day.

DETAILED DESCRIPTION OF THE INVENTION

[0023] An MAOB inhibitor according to this invention is a compound thatinhibits MAOB but causes much less or no inhibition of MAOA activity, ora compound that selectively inhibits MAOB (e.g., within a particulardosage range). Hereinafter, the activity of an MAOB inhibitor as usedaccording to this invention will be referred to as “selective MAOBinhibitor activity.”

[0024] In one embodiment, the MAOB inhibitor is selected from the groupconsisting of selegiline (Jumex®, Jumexal® Carbex®, Eldepryl®,Movergan®; Aptapryl®, Anipryl®; Eldeprine®; Plurimen®),desmethylselegiline, pargyline (Eudatin®, Supirdyl®, Eutonyl®) [U.S.Pat. No. 3,155,584], rasagiline [R(+)N-propargyl-laminoindan],3-N-phenylacetylamino-2,5-piperidinedione, caroxyazone, AGN-1135 [WO92/21333], MDL 72195 [WO 92/21333], J 508 [WO 92/21333], lazabemide [WO00/45846], milacemide [WO 00/45846], IFO [WO 00/45846], mofegiline [WO00/45846], and5-(4-(4,4,4-trifluorobutoxy)phenyl)-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one[WO 00/45846]. In another embodiment, prodrugs or metabolites of theMAOB inhibitors are contemplated. Said metabolite should havesubstantially the same or better selective MAOB inhibitor activity asits unmetabolized form.

[0025] A prodrug of a MAOB inhibitor is a derivatized MAOB inhibitorthat is metabolized in vivo into the active inhibitory agent. Prodrugsaccording to this invention preferably have substantially the same orbetter therapeutic value than the underivatized MAOB inhibitor. Forexample, a prodrug useful according to this invention can improve thepenetration of the drug across biological membranes leading to improveddrug absorption; prolong duration of the action of the drug, e.g., slowrelease of the parent drug from the prodrug and/or decrease first-passmetabolism of the drug; target the drug action; improve aqueoussolubility and stability of the drug (e.g., intravenous preparations,eyebrows etc.); improve topical drug delivery (e.g., dermal and oculardrug delivery); improve the chemical and/or enzymatic stability of drugs(e.g., peptides); or decrease side effects due to the drug. Methods formaking prodrugs are readily known in the art.

[0026] The term “MAOB inhibitor” according to this invention ormetabolite thereof, as used herein includes pharmaceutically acceptablesalts of those compounds. Pharmaceutically acceptable salts of MAOBinhibitors useful according to the methods of this invention are saltsprepared from pharmaceutically acceptable reagents. In one embodiment,said pharmaceutically acceptable salt is a hydrochloride salt.

[0027] Methods known in the art for evaluating the activity of MAOB andMAOA can be used for selecting MAOB inhibitors according to thisinvention. For example, blood samples can be drawn to determine plateletMAO activity using radiolabelled benzylamine or phenylethylamine. (i.e.,evaluating MAOB inhibitory activity). [Murphy, D. L., et al.,Psychopharm. 62:129-132 (1979); Murphy, D. L., et al., Biochem. Med.16:254-265 (1976); all incorporated by reference herein] In oneembodiment, MAOB activity is decreased greater than 80% compared to MAOBenzyme activity before treatment. In a preferred embodiment, MAOBactivity is decreased greater than 90% or 95% compared to MAOB activitybefore treatment.

[0028] MAOA inhibitory activity can, for example, be evaluated bymeasuring levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) or5-hydroxyindoleacetic acid (5-HIAA) in the plasma of blood or incerebral spinal fluid (CSF) by using gas chromatography-massspectroscopy (gc-ms). [Murphy, D. L., et al., Clinical Pharmacology inPsychiatry, 3rd Series., Eds. Dahl, Gram, Paul, and Potter,Springer-Verlag: 1987; Major, L. F., et al., J. Neurochem. 39:229-231(1979); Jimerson, D. C., et al., Biomed. Mass. Spectrom. 8:256-259(1981); all incorporated by reference herein]. In one embodiment, afteradministration of the MAOB inhibitor, plasma MHPG levels should not bereduced lower than 45% of pretreatment levels of plasma MHPG. In apreferred embodiment, after administration of the MAOB inhibitor, plasmaMHPG or CSF 5-HIAA levels should not be reduced more than 80% ofpretreatment levels of MHPG or 5-HIAA levels, respectively.

[0029] ALDH inhibitors according to the invention are compounds that arecapable of inhibiting the activity of one or more of the severalisozymes of ALDH, e.g., ALDH-I and ALDH-II. According to one embodiment,the ALDH is involved in alcohol metabolism. ALDH inhibitors according tothis invention include, e.g., disulfiram, coprine, cyanamide,1-aminocyclopropanol (ACP), daidzin, cephalosporins, antidiabeticsulfonyl ureas, metronidazole, and any of their metabolites or analogsexhibiting ALDH-inhibiting activity. In another embodiment, the ALDHinhibitor is disulfiram or an ALDH-inhibiting metabolite thereof. Suchmetabolites include, e.g., S-methyl N,N-diethyldithiocarbamate, S-methylN,N-diethyldithiocarbamate sulfoxide, and S-methylN,N-diethylthiocarbamate sulfoxide.

[0030] The term “ALDH inhibitor” according to the invention ormetabolite thereof, as used herein, includes pharmaceutically acceptablesalts of those compounds.

[0031] The term “alcoholism” according to the invention includes alcoholabuse and alcohol dependence as described below.

[0032] The term “alcohol abuse” is defined in the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV). Alcohol abuse as amaladaptive pattern of alcohol use that leads to clinically significantimpairment or distress. Symptoms include one or more of the followingoccurring within a 12-month period: (1) recurrent alcohol use thatresults in a failure to fulfill major role obligations at work, schoolor home; (2) recurrent alcohol use in physically hazardous situations;(3) recurrent alcohol-related legal problems; and (4) continued alcoholuse despite having persistent or recurrent social or interpersonalproblems caused or exacerbated by the effects of the substance [McRae etal., supra; Swift, R. M., supra; Kick, S., supra].

[0033] Alcohol dependence occurs when symptoms of abuse are accompaniedby three or more of the following: (1) tolerance defined by either: (a)a need for markedly increased amounts of alcohol to achieve intoxicationor desired effect, or (b) markedly diminished effect with continued useof the same amount of alcohol; (2) withdrawal manifested by either: (a)characteristic withdrawal syndrome for alcohol or (b) alcohol taken torelieve or avoid withdrawal symptoms; (3) alcohol taken in largeramounts over a longer period than as intended; (4) a persistent desireor unsuccessful efforts to reduce or control drinking; (5) much timespent in activities necessary to obtain alcohol, use alcohol, or recoverfrom its effects; (6) important social, occupational, or recreationalactivities being given up or reduced because of drinking; and (7)continued use despite knowledge of having a persistent or recurrentphysical or psychological problem caused or exacerbated by alcohol[McRae et al., supra; Swift, R. M., supra; Kick, S., supra].

[0034] Alcohol abuse or dependence can also result in other symptomsincluding dyspepsia or epigastric pain, headache, diarrhea, difficultyin sleeping, fatigue, unexplained weight loss, apparent malnutrition,easy bruising, increased mean corpuscular volume, elevated transaminaselevels (especially an aspartate transaminase level greater than ofalanine transaminase), elevated y-glutamyl transferase levels,iron-deficiency anemia, hepatomegaly, jaundice, spider angiomata,ascites, and peripheral edema. Behavioral symptoms associated withalcohol abuse or dependence include absenteeism from work or school,increasing irritability, difficulties with relationships, verbal orphysical abuse, and depression [McRae et al., supra; Swift, R. M.,supra; Kick, S., supra].

[0035] Alcoholism is often diagnosed using questionnaires, known tothose of ordinary skill in the art, which are structured to obtaininformation related to the symptoms of alcohol abuse and/or dependenceas outlined by the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV). The most commonly used screening test used for detectingalcohol abuse or dependence is the CAGE questionnaire [Kick, S., supra].Alcoholics Anonymous describes another questionnaire.

[0036] A patient to be treated for, or protected against, the onset ofalcoholism according to this invention can be a human, includingchildren and adults, who are susceptible to or are suffering fromalcoholism or who are being treated for alcoholism and are susceptibleto experiencing relapses. A patient who is having difficulty complyingwith, or is being induced to comply with, treatments using ALDHinhibitors or their active metabolites according to this invention canbe a human, including children and adults.

[0037] Compositions according the present invention comprise apharmaceutically acceptable carrier together with an ALDH inhibitor andan MAOB inhibitor. According to one embodiment, the ALDH inhibitor isdisulfiram, or a metabolite or prodrug thereof. According to anotherembodiment, the composition comprises 500 mg, 250 mg, 125 mg, or 60 mgof disulfiram, or metabolite or prodrug thereof. According to yetanother embodiment, the MAOB inhibitor is selegiline, or a metabolite orprodrug thereof. According to a further embodiment, the compositioncomprises 15 mg or less of selegiline, or metabolite or prodrug thereof.

[0038] In a preferred embodiment, the composition comprises 500 mg, 250mg, 125 mg or 60 mg of disulfiram, or metabolite or prodrug thereof, and15 mg or less of selegiline, or metabolite or prodrug thereof. In a morepreferred embodiment, the composition comprises about 60 mg ofdisulfiram, or a metabolite or prodrug thereof, and about 2 mg ofselegiline, or a metabolite or prodrug thereof.

[0039] The effective dosage of a composition of the inventionadministered to a patient is at least an amount required to minimize,reduce or eliminate one or more symptoms associated with preventing ortreating alcoholism, typically one of the symptoms discussed above. Themagnitude of a prophylactic or therapeutic dose of the composition ofthe invention in the treatment of a patient will vary with the symptomsbeing exhibited, the severity of the patient's affliction, the desireddegree of therapeutic response, the route of administration, and theconcomitant therapies being administered. The dose and dose frequencywill also vary according to the age, weight and response of theindividual patient. Generally, however, treatment for alcoholism will beongoing, although the intensity of treatment can vary depending on thepatient's condition and exposure to biochemical and environmentalstimuli that can warrant a variation on the treatment. Dosages can beadministered in a single or multiple dosage regimen.

[0040] According to one preferred embodiment of the invention, thecomposition comprising 500 mg, 250 mg, 125 mg or 60 mg of disulfiram and15 mg or less selegiline is administered twice a day, in the morning andat noon or late afternoon. In another preferred embodiment, acomposition comprising about 125 mg of disulfiram and about 5 mg ofselegiline is administered twice a day, in the morning and at noon orlate afternoon.

[0041] Selegiline can be administered twice a day, in the morning and atnoon or late afternoon. An initial daily non-oral dose can be at leastabout 0.01 mg per kg of body weight, calculated on the basis of the freesecondary amine, with progressively higher doses being employeddepending upon the response to therapy. The final daily dose can bebetween about 0.05 mg/kg of body weight to about 0.15 mg/kg of bodyweight (all such doses being calculated in the basis of the freesecondary amine).

[0042] The present invention when employing selegiline is not limited toa particular form of selegiline and the drug can be used either as afree base or as a pharmaceutically acceptable acid addition salt. In thelatter case, the hydrochloride salt is preferred. However, other saltsuseful in the invention include those derived from organic and inorganicacids such as, without limitation, hydrobromic acid, phosphoric acid,sulfuric acid, methane sulfonic acid, acetic acid, tartaric acid, lacticacid, succinic acid, citric acid, malic acid, maleic acid, aconiticacid, salicylic acid, thalic acid, embonic acid, enanthic acid, and thelike.

[0043] The treating physician will know how to increase, decrease orinterrupt treatment based upon the patient's response. Improvement foralcoholics or potentially relapsing alcoholics can be assessed byobserving increased abstinence from consuming alcohol by the patient,following the methods of this invention, as compared to patients wheretherapy did not comprise the co-administration of a MAOB inhibitor.Improvement in compliance with self-administering ALDH inhibitors can beassessed by observing the increased duration over which patients,following the methods of this invention, take the ALDH inhibitor ascompared to patients whose therapy did not comprise theco-administration of an MAOB inhibitor.

[0044] Any suitable route of administration can be employed forproviding the patient with an effective dosage of a composition of thisinvention. For example, oral, peroral, buccal, nasal, pulmonary,vaginal, lingual, sublingual, rectal, parenteral, transdermal,intraocular, intravenous, intraarterial, intracardial intramuscular,intraperitoneal, intracutaneous, subcutaneous, sublingual, intranasal,intramuscular, and intrathecal administration and the like can beemployed as appropriate. The term parenteral as used herein includessubcutaneous, intracutaneous, intravenous, intramuscular,intra-articular, intrasynovial, intrasternal, intrathecal, intralesionaland intracranial injection or infusion techniques. According to onepreferred aspect of this invention, the route of administration is theoral route.

[0045] The composition can be conveniently presented in unit dosage formand prepared by any of the methods well-known in the art of pharmacy.Dosage forms can include tablets, scored tablets, coated tablets, pills,caplets, capsules (e.g., hard gelatin capsules), troches, dragees,powders, aerosols, suppositories, parenterals, dispersions, suspensions,solutions, transdermal patches and the like, including sustained releaseformulations well known in the art. In one preferred embodiment, thedosage form is a scored tablet or a transdermal patch. U.S. Pat. No.5,192,550, incorporated herein by reference, describes a dosage form forselegiline comprising an outer wall with one or more pores, in which thewall is impermeable to selegiline but permeable to external fluids. Thisdosage form can have applicability for oral, sublingual or buccaladministration.

[0046] The compositions of this invention can be orally administered inany orally acceptable dosage form including, but not limited to,capsules, tablets, and aqueous suspensions and solutions. In the case oftablets for oral use, carriers which are commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsare administered orally, the active ingredient (i.e., ALDH inhibitorand/or MAOB inhibitor) is combined with emulsifying and suspendingagents. If desired, certain sweetening and/or flavoring and/or coloringagents can be added.

[0047] The compositions according to this invention can be in the formof a sterile injectable preparation, for example, as a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that canbe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil can be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions can also contain a long-chain alcohol diluent or dispersantsuch as Ph. Helv or a similar alcohol.

[0048] Methods for making transdermal patches including selegilinetransdermal patches have been described in the art. [See e.g., U.S. Pat.Nos. 4,861,800; 4,868,218; 5,128,145; 5,190,763; and 5,242,950; and EP-A404807, EP-A 509761, EP-A 593807, and EP-A 5509761, all of which areincorporated by reference herein.]

[0049] Compositions of this invention can also be administered in theform of suppositories for rectal administration. These compositions canbe prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

[0050] The compositions of this invention can be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and canbe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

[0051] Patients can be regularly evaluated by physicians, e.g., once aweek, to determine whether there has been an improvement in symptoms andwhether the dosage of the composition of the invention needs to beadjusted.

[0052] According to the methods of this invention, the MAOB inhibitorcan be included in the composition comprising the ALDH inhibitor.Alternatively, the MAOB inhibitor can be administered simultaneouslywith the composition comprising the ALDH inhibitor, or at any timeduring the treatment of the patient with the ALDH inhibitor.

[0053] The various terms described above such as “therapeuticallyeffective amount,” are encompassed by the above-described dosage amountsand dose frequency schedule. Generally, a therapeutically effectiveamount of an MAOB inhibitor is that amount at which MAOB is inhibitedbut MAOA exhibits slight or no reduction in activity in the patient.Slight reduction in activity preferably comprises less than about 30%reduction in activity, more preferably less than about 20% reduction inactivity, and yet more preferably less than about 10% reduction inactivity. In one embodiment, the dosage of selegiline is an amount equalto or less than 15 mg per day. In another embodiment, the dosage ofpargyline is equal to or less than 30 mg/day.

[0054] Throughout this specification, the word “comprise” or variationssuch as “comprises” or “comprising” will be understood to imply theinclusion of a stated integer or group of integers but not the exclusionof any other integer or group of integers.

Statement Regarding Preferred Embodiments

[0055] While the invention has been described with respect to preferredembodiments, those skilled in the art will readily appreciate thatvarious changes and/or modifications can be made to the inventionwithout departing from the spirit or scope of the invention as definedby the appended claims. All documents cited herein are incorporated intheir entirety herein.

What is claimed is:
 1. A composition comprising a monoamine oxidase B(MAOB) inhibitor and an aldehyde dehydrogenase (ALDH) inhibitor.
 2. Thecomposition according to claim 1, wherein the aldehyde dehydrogenaseinhibitor inhibits the activity of aldehyde dehydrogenase-I.
 3. Thecomposition according to claim l, wherein the aldehyde dehydrogenaseinhibitor is selected from the group consisting: of disulfiram, coprine,cyanamide, 1-aminocyclopropanol, daidzin, cephalosporin, antidiabeticsulfonyl urea, metronidazole, and metabolites or analogs thereof thatexhibit aldehyde dehydrogenase-inhibiting activity.
 4. The compositionaccording to claim 1, wherein the aldehyde dehydrogenase is disulfiramor a metabolite or analog thereof that exhibits aldehydedehydrogenase-inhibiting activity.
 5. The composition according to claim1, wherein the composition comprises an amount of disulfiram selectedfrom the group consisting of: about 500 mg, about 250 mg, about 125 mgand about 60 mg of disulfiram.
 6. The composition according to claim 1,wherein the monoamine oxidase B inhibitor is selected from the groupconsisting of: selegiline, pargyline, desmethylselegiline, rasagiline,3-N-phenylacetylamino-2,5-piperidinedione and caroxyazone.
 7. Thecomposition according to of claim 1, wherein the monoamine oxidaseinhibitor B is selegiline.
 8. The composition according to claim 7,wherein the composition comprises an amount of selegiline selected fromthe group consisting of: about 15 mg or less, about 10 mg or less, about5 mg or less, about 2.5 or less and about 1 or less mg of selegiline. 9.The composition according to claim 1, wherein the monoamine oxidaseinhibitor B is selegiline and the aldehyde dehydrogenase inhibitor isdisulfiram.
 10. A method for preventing, treating or reducing alcoholismin a patient in need for treatment thereof comprising the step ofadministering a therapeutically effective amount of a compositioncomprising a monoamine oxidase B inhibitor and an aldehyde dehydrogenaseinhibitor.
 11. The method of claim 10 wherein the aldehyde dehydrogenaseinhibitor inhibits aldehyde dehydrogenase-I.
 12. The method according toclaim 10, wherein the aldehyde dehydrogenase inhibitor is selected fromthe group consisting of: disulfiram, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporin, antidiabetic sulfonylurea, metronidazole, and metabolites or analogs thereof exhibitingaldehyde dehydrogenase-inhibiting activity.
 13. The method according toclaim 10, wherein the aldehyde dehydrogenase inhibitor is disulfiram, ora metabolite or analog thereof that exhibitsaldehyde-dehydrogenase-inhibiting activity.
 14. The method according toclaim 13, wherein the amount of disulfiram administered to said patientper day is selected from the group consisting of about 500 mg, about 250mg, about 125 mg and about 60 mg.
 15. The method according to claim 10,wherein the monoamine oxidase B inhibitor is selected from the groupconsisting of: selegiline, pargyline, desmethylselegiline, rasagiline,3-N-phenylacetylamino-2,5-piperidinedione and caroxyazone.
 16. Themethod according to claim 10, wherein the monoamine oxidase B inhibitoris selegiline.
 17. The method according to claim 16, wherein the amountof selegiline administered to said patient per day is selected from thegroup consisting of: 15 mg or less, 10 mg or less, 5 mg or less, 2.5 mgor less, and 1 mg or less of selegiline.
 18. The method according toclaim 10, wherein the monoamine oxidase inhibitor B is selegiline andthe aldehyde dehydrogenase inhibitor is disulfiram.
 19. The methodaccording to claim 10, wherein the composition is administered orally,parentally or transdermally.
 20. The method according to claim 19,wherein the composition is administered as a capsule, a tablet or atransdermal patch.
 21. The method according to claim 10, wherein thepatient is a human.
 22. A method of increasing patient compliance with atherapeutic regimen comprising self-administration of an aldehydedehydrogenase inhibitor, comprising the step of administering to thepatient a therapeutically effective amount of a monoamine oxidase Binhibitor.
 23. The method according to claim 22, wherein the patientsuffers with alcoholism.
 24. The method according to claim 22, whereinthe aldehyde dehydrogenase inhibitor inhibits aldehyde dehydrogenase-I.25. The method according to claim 22, wherein the aldehyde dehydrogenaseinhibitor is selected from the group consisting of: disulfiram, coprine,cyanamide, 1-aminocyclopropanol, daidzin, cephalosporin, antidiabeticsulfonyl urea, metronidazole, and metabolites or analogs thereofexhibiting aldehyde dehydrogenase-inhibiting activity.
 26. The methodaccording to claim 22, wherein the aldehyde dehydrogenase inhibitor isdisulfiram, or a metabolite or analog thereof that exhibitsaldehyde-dehydrogenase-inhibiting activity.
 27. The method according toclaim 26, wherein the amount of disulfiram administered to said patientper day is selected from the group consisting of about 500 mg, about 250mg, about 125 mg and about 60 mg.
 28. The method according to claim 22,wherein the monoamine oxidase B inhibitor is selected from the groupconsisting of: selegiline, pargyline, desmethylselegiline, rasagiline,3-N-phenylacetylamino-2,5-piperidinedione and caroxyazone.
 29. Themethod according to claim 22, wherein the monoamine oxidase B inhibitoris selegiline.
 30. The method according to claim 29, wherein the amountof selegiline administered to said patient per day is selected from thegroup consisting of: 15 mg or less, 10 mg or less, 5 mg or less, 2.5 mgor less, and 1 mg or less of selegiline.
 31. The method according toclaim 22, wherein the monoamine oxidase inhibitor B is selegiline andthe aldehyde dehydrogenase inhibitor is disulfiram.
 32. The methodaccording to claim 31, wherein the composition is administered orally,parentally or transdermally.
 33. The method according to claim 32,wherein the composition is administered as a capsule, a tablet or atransdermal patch.
 34. The method according to claim 22, wherein thepatient is a human.